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Adiwidjaja J, Spires J, Brouwer KLR. Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD). Pharm Res 2024; 41:441-462. [PMID: 38351228 DOI: 10.1007/s11095-024-03664-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/18/2024] [Indexed: 03/13/2024]
Abstract
PURPOSE This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of disease-related changes in drug pharmacokinetics. METHODS A virtual NAFLD patient population was developed in GastroPlus (v.9.8.2) by accounting for pathophysiological changes associated with the disease and proteomics-informed alterations in the abundance of metabolizing enzymes and transporters pertinent to drug disposition. The NAFLD population model was verified using exemplar drugs where elimination is influenced predominantly by cytochrome P450 (CYP) enzymes (chlorzoxazone, caffeine, midazolam, pioglitazone) or by transporters (rosuvastatin, 11C-metformin, morphine and the glucuronide metabolite of morphine). RESULTS PBPK model predictions of plasma concentrations of all the selected drugs and hepatic radioactivity levels of 11C-metformin were consistent with the clinically-observed data. Importantly, the PBPK simulations using the virtual NAFLD population model provided reliable estimates of the extent of changes in key pharmacokinetic parameters for the exemplar drugs, with mean predicted ratios (NAFLD patients divided by healthy individuals) within 0.80- to 1.25-fold of the clinically-reported values, except for midazolam (prediction-fold difference of 0.72). CONCLUSION A virtual NAFLD population model within the PBPK framework was successfully developed with good predictive capability of estimating disease-related changes in drug pharmacokinetics. This supports the use of a PBPK modeling approach for prediction of the pharmacokinetics of new investigational or repurposed drugs in patients with NAFLD and may help inform dose adjustments for drugs commonly used to treat comorbidities in this patient population.
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Affiliation(s)
- Jeffry Adiwidjaja
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Simulations Plus, Inc, Lancaster, CA, USA
| | | | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Powell-Brett S, Hall L, Edwards M, Roberts K. A systematic review and meta-analysis of the accuracy and methodology of the 13C mixed triglyceride breath test for the evaluation of pancreatic function. Pancreatology 2023; 23:283-293. [PMID: 36805050 DOI: 10.1016/j.pan.2023.02.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/31/2023] [Accepted: 02/13/2023] [Indexed: 02/23/2023]
Abstract
INTRODUCTION The diagnosis of pancreatic exocrine insufficiency (PEI) is challenging. The 13C mixed triglyceride breath test (13C MTGT) has emerged as a promising diagnostic method. However, there is need to assimilate high quality evidence to understand its accuracy and address variation in the conduct of the test. This systematic review aims to appraise the existing literature on the methodology and accuracy of the 13C MTGT. METHODS A systematic literature search of PUBMED, MEDLINE, and EMBASE databases identified articles describing the use of the 13C MTGT in the analysis of pancreatic function in adults. Data extraction addressed each methodological step in detail. These were combined in a narrative synthesis. For quantitative analysis, those studies within this search that assessed the accuracy of the 13C MTGT were selected. RESULTS 37 studies were included for qualitative review, 6 assessed sensitivity and specificity of the 13C MTGT against another measure of PEI and were included in quantitative synthesis. Areas with a majority consensus were pre-test overnight fasting, a test meal with a lipid load of at least 10 g, within-test control of exercise and dietary intake, breath sampling every 30 min and the preference of isotope ratio mass spectrometry (IRMS) for analysis. Good evidence suggests there is no benefit to extend the total timeframe of breath sampling beyond 6 h. Areas of uncertainty are a) Duration of PERT cessation b) the addition of metoclopramide, c) the ideal test meal and d) if the time frame can be shortened. Quantitative analysis among 6 studies demonstrated a pooled sensitivity and specificity of the 13C MTGT for diagnosing PEI of 0.84 (95% CI: 0.73-0.91) and 0.87 (95% CI: 0.79-0.93) respectively. CONCLUSION There is yet to emerge a clear standard of breath test methodology that is validated for all causes of PEI and suitable for routine use. The accuracy of the 13C MTGT for diagnosing PEI is encouraging when compared to other measures. We present a suggested set protocol based on the current literature and identify areas that need further, high quality evidence. With refinement, the 13C MTGT could become a valuable, non-invasive PEI diagnostic tool that could be used outside of specialist centres.
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Affiliation(s)
- Sarah Powell-Brett
- Department of Hepatobiliary, Pancreatic and Transplant Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
| | - Lewis Hall
- Department of Hepatobiliary, Pancreatic and Transplant Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Michael Edwards
- Department of Hepatobiliary, Pancreatic and Transplant Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Keith Roberts
- Department of Hepatobiliary, Pancreatic and Transplant Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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Kurata Y, Muraki S, Hirota T, Araki H, Ieiri I. Effect of Liver Cirrhosis on Theophylline Trough Concentrations: A Comparative Analysis of Organ Impairment Using Child-Pugh and MELD Scores. Br J Clin Pharmacol 2022; 88:3819-3828. [PMID: 35338501 DOI: 10.1111/bcp.15333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 03/09/2022] [Accepted: 03/16/2022] [Indexed: 11/29/2022] Open
Abstract
AIMS Theophylline clearance is known to be reduced in patients with chronic liver diseases (CLDs) such as chronic hepatitis (CH) and liver cirrhosis (LC). The Child-Pugh (CP) score is generally used for pharmacokinetic evaluation, whilst a model for end-stage liver disease (MELD) has not yet been fully evaluated. This study aimed to predict theophylline clearance in patients with LC classified based on CP and MELD scores by population pharmacokinetic (PPK) analysis. METHODS PPK analysis included 433 steady-state trough concentrations from 192 Japanese bronchial asthma patients with and without CLDs and was performed using NONMEM. The severity of LC was assessed by CP and MELD scores. RESULTS The final CP and MELD models which described apparent theophylline clearance (CL/F) were obtained. The CP model showed that the mean CL/F in patients without CLDs, CH patients, and LC patients with CP class A, B, and C was 0.0473, 0.0413, 0.0330, 0.0280, and 0.0209 L/h kg-1, respectively. The MELD model predicted that CL/F in patients without CLDs, CH patients, and LC patients with MELD scores of < 10, 10-14, 15-19, 20-24, and ≥ 25 was 0.0472, 0.0413, 0.0324, 0.0268, 0.0230, 0.0197, and 0.0155 L/h kg-1, respectively. CONCLUSIONS CL/F in various stages of LC was evaluated, and a change in CL/F was highly dependent on the severity of CLDs in both models. The MELD model provided a more accurate and precise description of theophylline clearance in LC than the CP model, which may be due to the wider dynamic range of the MELD score.
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Affiliation(s)
- Yasuo Kurata
- Department of Pharmacy, Fukuoka City Hospital, Fukuoka City Hospital Organization, Local Incorporated Administrative Agency, Fukuoka, Japan
| | - Shota Muraki
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Hirota
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.,Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan
| | - Hiroshi Araki
- Department of Pharmacy, Fukuoka City Hospital, Fukuoka City Hospital Organization, Local Incorporated Administrative Agency, Fukuoka, Japan
| | - Ichiro Ieiri
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.,Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan
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Grzegorzewski J, Bartsch F, Köller A, König M. Pharmacokinetics of Caffeine: A Systematic Analysis of Reported Data for Application in Metabolic Phenotyping and Liver Function Testing. Front Pharmacol 2022; 12:752826. [PMID: 35280254 PMCID: PMC8914174 DOI: 10.3389/fphar.2021.752826] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 12/03/2021] [Indexed: 01/13/2023] Open
Abstract
Caffeine is by far the most ubiquitous psychostimulant worldwide found in tea, coffee, cocoa, energy drinks, and many other beverages and food. Caffeine is almost exclusively metabolized in the liver by the cytochrome P-450 enzyme system to the main product paraxanthine and the additional products theobromine and theophylline. Besides its stimulating properties, two important applications of caffeine are metabolic phenotyping of cytochrome P450 1A2 (CYP1A2) and liver function testing. An open challenge in this context is to identify underlying causes of the large inter-individual variability in caffeine pharmacokinetics. Data is urgently needed to understand and quantify confounding factors such as lifestyle (e.g., smoking), the effects of drug-caffeine interactions (e.g., medication metabolized via CYP1A2), and the effect of disease. Here we report the first integrative and systematic analysis of data on caffeine pharmacokinetics from 141 publications and provide a comprehensive high-quality data set on the pharmacokinetics of caffeine, caffeine metabolites, and their metabolic ratios in human adults. The data set is enriched by meta-data on the characteristics of studied patient cohorts and subjects (e.g., age, body weight, smoking status, health status), the applied interventions (e.g., dosing, substance, route of application), measured pharmacokinetic time-courses, and pharmacokinetic parameters (e.g., clearance, half-life, area under the curve). We demonstrate via multiple applications how the data set can be used to solidify existing knowledge and gain new insights relevant for metabolic phenotyping and liver function testing based on caffeine. Specifically, we analyzed 1) the alteration of caffeine pharmacokinetics with smoking and use of oral contraceptives; 2) drug-drug interactions with caffeine as possible confounding factors of caffeine pharmacokinetics or source of adverse effects; 3) alteration of caffeine pharmacokinetics in disease; and 4) the applicability of caffeine as a salivary test substance by comparison of plasma and saliva data. In conclusion, our data set and analyses provide important resources which could enable more accurate caffeine-based metabolic phenotyping and liver function testing.
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Breath-Taking Perspectives and Preliminary Data toward Early Detection of Chronic Liver Diseases. Biomedicines 2021; 9:biomedicines9111563. [PMID: 34829792 PMCID: PMC8615034 DOI: 10.3390/biomedicines9111563] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 12/17/2022] Open
Abstract
The gold standard method for chronic liver diseases diagnosis and staging remains liver biopsy, despite the spread of less invasive surrogate modalities based on imaging and blood biomarkers. Still, more than 50% of chronic liver disease cases are detected at later stages when patients exhibit episodes of liver decompensation. Breath analysis represents an attractive means for the development of non-invasive tests for several pathologies, including chronic liver diseases. In this perspective review, we summarize the main findings of studies that compared the breath of patients with chronic liver diseases against that of control subjects and found candidate biomarkers for a potential breath test. Interestingly, identified compounds with best classification performance are of exogenous origin and used as flavoring agents in food. Therefore, random dietary exposure of the general population to these compounds prevents the establishment of threshold levels for the identification of disease subjects. To overcome this limitation, we propose the exogenous volatile organic compounds (EVOCs) probe approach, where one or multiple of these flavoring agent(s) are administered at a standard dose and liver dysfunction associated with chronic liver diseases is evaluated as a washout of ingested compound(s). We report preliminary results in healthy subjects in support of the potential of the EVOC Probe approach.
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Keller J, Hammer HF, Afolabi PR, Benninga M, Borrelli O, Dominguez‐Munoz E, Dumitrascu D, Goetze O, Haas SL, Hauser B, Pohl D, Salvatore S, Sonyi M, Thapar N, Verbeke K, Fox MR, European 13C‐breath test group. European guideline on indications, performance and clinical impact of 13 C-breath tests in adult and pediatric patients: An EAGEN, ESNM, and ESPGHAN consensus, supported by EPC. United European Gastroenterol J 2021; 9:598-625. [PMID: 34128346 PMCID: PMC8259225 DOI: 10.1002/ueg2.12099] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/06/2021] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION 13 C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. METHODS This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of 13 C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and <10% disagreed. RESULTS The guideline gives an overview over general methodology of 13 C-breath testing and provides recommendations for the use of 13 C-breath tests to diagnose Helicobacter pylori infection, measure gastric emptying time, and monitor pancreatic exocrine and liver function in adult and pediatric patients. Other potential applications of 13 C-breath testing are summarized briefly. The recommendations specifically detail when and how individual 13 C-breath tests should be performed including examples for well-established test protocols, patient preparation, and reporting of test results. CONCLUSION This clinical practice guideline should improve pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, this guideline identifies areas of future clinical research involving the use of 13 C-breath tests.
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Affiliation(s)
- Jutta Keller
- Department of Internal MedicineIsraelitic HospitalAcademic Hospital University of HamburgHamburgGermany
| | - Heinz F. Hammer
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
| | - Paul R. Afolabi
- NIHR Southampton Biomedical Research CentreUniversity Hospital Southampton NHS Foundation Trust and University of SouthamptonSouthamptonUK
| | - Marc Benninga
- Department of Pediatric Gastroenterology, Hepatology and NutritionEmma Children's HospitalAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Osvaldo Borrelli
- UCL Great Ormond Street Institute of Child Health and Department of GastroenterologyNeurogastroenterology and MotilityGreat Ormond Street HospitalLondonUK
| | - Enrique Dominguez‐Munoz
- Department of Gastroenterology and HepatologyUniversity Hospital of Santiago de CompostelaSantiagoSpain
| | | | - Oliver Goetze
- Department of Medicine IIDivision of HepatologyUniversity Hospital WürzburgWürzburgGermany
| | - Stephan L. Haas
- Department of Upper GI DiseasesKarolinska University HospitalStockholmSweden
| | - Bruno Hauser
- Department of Paediatric Gastroenterology, Hepatology and NutritionKidZ Health Castle UZ BrusselsBrusselsBelgium
| | - Daniel Pohl
- Division of Gastroenterology and HepatologyUniversity Hospital ZürichZürichSwitzerland
| | - Silvia Salvatore
- Pediatric DepartmentHospital "F. Del Ponte"University of InsubriaVareseItaly
| | - Marc Sonyi
- Department of Internal MedicineDivision of Gastroenterology and HepatologyMedical University of GrazGrazAustria
- Clinic for General Medicine, Gastroenterology, and Infectious DiseasesAugustinerinnen HospitalCologneGermany
| | - Nikhil Thapar
- UCL Great Ormond Street Institute of Child Health and Department of GastroenterologyNeurogastroenterology and MotilityGreat Ormond Street HospitalLondonUK
- Department of Gastroenterology, Hepatology and Liver TransplantationQueensland Children's HospitalBrisbaneAustralia
| | - Kristin Verbeke
- Translational Research Center for Gastrointestinal DisordersKU LeuvenLeuvenBelgium
| | - Mark R. Fox
- Division of Gastroenterology and HepatologyUniversity Hospital ZürichZürichSwitzerland
- Digestive Function: Basel, Laboratory and Clinic for Motility Disorders and Functional Gastrointestinal DiseasesCentre for Integrative GastroenterologyKlinik ArlesheimArlesheimSwitzerland
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Neuroprotective Effects of Coffee Bioactive Compounds: A Review. Int J Mol Sci 2020; 22:ijms22010107. [PMID: 33374338 PMCID: PMC7795778 DOI: 10.3390/ijms22010107] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023] Open
Abstract
Coffee is one of the most widely consumed beverages worldwide. It is usually identified as a stimulant because of a high content of caffeine. However, caffeine is not the only coffee bioactive component. The coffee beverage is in fact a mixture of a number of bioactive compounds such as polyphenols, especially chlorogenic acids (in green beans) and caffeic acid (in roasted coffee beans), alkaloids (caffeine and trigonelline), and the diterpenes (cafestol and kahweol). Extensive research shows that coffee consumption appears to have beneficial effects on human health. Regular coffee intake may protect from many chronic disorders, including cardiovascular disease, type 2 diabetes, obesity, and some types of cancer. Importantly, coffee consumption seems to be also correlated with a decreased risk of developing some neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and dementia. Regular coffee intake may also reduce the risk of stroke. The mechanism underlying these effects is, however, still poorly understood. This review summarizes the current knowledge on the neuroprotective potential of the main bioactive coffee components, i.e., caffeine, chlorogenic acid, caffeic acid, trigonelline, kahweol, and cafestol. Data from both in vitro and in vivo preclinical experiments, including their potential therapeutic applications, are reviewed and discussed. Epidemiological studies and clinical reports on this matter are also described. Moreover, potential molecular mechanism(s) by which coffee bioactive components may provide neuroprotection are reviewed.
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Ishii M, Ishii Y, Nakayama T, Takahashi Y, Asai S. 13C-caffeine breath test identifies single nucleotide polymorphisms associated with caffeine metabolism. Drug Metab Pharmacokinet 2020; 35:321-328. [PMID: 32303460 DOI: 10.1016/j.dmpk.2020.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 02/25/2020] [Accepted: 03/08/2020] [Indexed: 12/18/2022]
Abstract
We performed a caffeine (N-3-methyl-13C) breath test (CafeBT) to determine whether it can be employed to identify caffeine metabolism-associated single nucleotide polymorphisms. The study included 130 healthy adults (mean age: 21.9 years). Saliva was collected using an Oragene®•DNA saliva collection kit. Breath samples were collected from the subjects. The subjects orally ingested 100 mg 13C-caffeine dissolved in distilled water. Subsequently, breath samples were collected in bags every 10 min for a total of 90 min. An analysis of 13CO2 in the expired breath was performed by infrared spectroscopy, and the sum of Δ13CO2 over 90 min (S90m) was calculated. DNA from saliva samples was genotyped using TaqMan® SNP Genotyping for the following genes: cytochrome P4501A2: rs762551, rs2472297, aryl-hydrocarbon receptor (rs4410790), and adenosine A2A receptor (rs5751876). All subjects had the genotype CC in rs2472297 alleles. No significant difference was observed in S90m among the genotypes of rs762551 and rs5751876; however, a significant difference was found in S90m among the genotypes of rs4410790 (C > T). Our findings suggest that the N-3 demethylation of caffeine is dependent on the rs4410790 allele and that CafeBT may be used to determine rs4410790 genotypes.
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Affiliation(s)
- Michiko Ishii
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine, Japan; Division of Research Planning and Development, Medical Research Support Center, Nihon University School of Medicine, Japan.
| | - Yukimoto Ishii
- Division of Research Planning and Development, Medical Research Support Center, Nihon University School of Medicine, Japan.
| | - Tomohiro Nakayama
- Division of Companion Diagnostics, Department of Pathology of Microbiology, Nihon University School of Medicine, Japan.
| | - Yasuo Takahashi
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Japan.
| | - Satoshi Asai
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine, Japan.
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Nehlig A. Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption. Pharmacol Rev 2018; 70:384-411. [PMID: 29514871 DOI: 10.1124/pr.117.014407] [Citation(s) in RCA: 318] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Most individuals adjust their caffeine intake according to the objective and subjective effects induced by the methylxanthine. However, to reach the desired effects, the quantity of caffeine consumed varies largely among individuals. It has been known for decades that the metabolism, clearance, and pharmacokinetics of caffeine is affected by many factors such as age, sex and hormones, liver disease, obesity, smoking, and diet. Caffeine also interacts with many medications. All these factors will be reviewed in the present document and discussed in light of the most recent data concerning the genetic variability affecting caffeine levels and effects at the pharmacokinetic and pharmacodynamic levels that both critically drive the level of caffeine consumption. The pharmacokinetics of caffeine are highly variable among individuals due to a polymorphism at the level of the CYP1A2 isoform of cytochrome P450, which metabolizes 95% of the caffeine ingested. Moreover there is a polymorphism at the level of another critical enzyme, N-acetyltransferase 2. At the pharmacodynamic level, there are several polymorphisms at the main brain target of caffeine, the adenosine A2A receptor or ADORA2. Genetic studies, including genome-wide association studies, identified several loci critically involved in caffeine consumption and its consequences on sleep, anxiety, and potentially in neurodegenerative and psychiatric diseases. We start reaching a better picture on how a multiplicity of biologic mechanisms seems to drive the levels of caffeine consumption, although much more knowledge is still required to understand caffeine consumption and effects on body functions.
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Affiliation(s)
- Astrid Nehlig
- INSERM U 1129, Pediatric Neurology, Necker-Enfants Malades Hospital, University of Paris Descartes, Inserm U1129, Paris, France
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Németh A. The coming of age of a young subspecialty: paediatric hepatology. Acta Paediatr 2017; 106:1742-1746. [PMID: 28321910 DOI: 10.1111/apa.13842] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 01/09/2017] [Accepted: 03/16/2017] [Indexed: 12/17/2022]
Abstract
Paediatric hepatology dates from the 1970s and it is the youngest of the organ-specific subspecialties. As then there have been impressive achievements in the fields of anatomical, metabolic, immunological and neoplastic diseases, and the advent of modern molecular biology has resulted in a marked increase in exact diagnoses. Liver transplants provided enormous stimulus for the discipline. Due to changing morbidity patterns, the discipline faces new challenges, such as environment- and lifestyle-induced liver diseases, but different forms of chronic viral hepatitis are diminishing. CONCLUSION High levels of competence require good clinical research, optimal results and a high degree of centralisation.
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Affiliation(s)
- Antal Németh
- Department of Clinical Science; Intervention and Technology; Karolinska Institutet and Karolinska University Hospital ALB Childrens′ Hospital-Huddinge; Stockholm Sweden
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Duan X, Shen G, Yang H, Lambert G, Wei F, Zhang JJ. Measurement of human CYP1A2 induction by inhalation exposure to benzo(a)pyrene based on in vivo isotope breath method. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2016; 208:506-511. [PMID: 26552516 DOI: 10.1016/j.envpol.2015.10.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 10/16/2015] [Accepted: 10/17/2015] [Indexed: 06/05/2023]
Abstract
Cytochrome P450 1A2 (CYP1A2) is an enzyme involved in the metabolic activation of certain carcinogens, and inducible by toxic substrates. To date, few studies have investigated in vivo CYP1A2 induction in humans and its relationship to polycylic aromatic hydrocarbons (PAHs) like benzo(a)pyrene (BaP). Non-smoking healthy male coke-oven workers (n = 30) were recruited as 'exposure' group, and non-smoking healthy office workers in the same city (n = 10) were selected as 'control' group, to test whether high inhalation exposure to PAHs can induce CYP1A2 activity in human livers. Significantly higher inhalation exposure of PAHs were found among the exposure group compared to the control. Inhalation BaP exposure concentration in the exposure group was more than 30 times higher than the control group (p < 0.001). However, the exposure group did not exhale significant higher levels of (13)CO2/(12)CO2 in breath samples (p = 0.81), and no significant relationship was found between the inhaled BaP concentration and the (13)CO2/(12)CO2 ratio (p = 0.91). A significant association was found between the (13)CO2/(12)CO2 exhalation and dietary BaP intake level. Hepatic CYP1A2 activity/induction level was not effected by inhaled BaP but was altered by ingestion of BaP.
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Affiliation(s)
- Xiaoli Duan
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China.
| | - Guofeng Shen
- Jiangsu Key Laboratory of Environmental Engineering, Jiangsu Provincial Research Academy of Environmental Sciences, Nanjing 210036, China
| | - Hongbiao Yang
- Anshan Environmental Monitoring Center, Liaoning 114004, China
| | - George Lambert
- University of Medicine and Dentistry of New Jersey/Rutgers University, Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
| | - Fusheng Wei
- China National Environmental Monitoring Center, Beijing 100012, China
| | - Junfeng Jim Zhang
- Nicholas School of the Environment and Global Health Institute, Duke University, NC 27708, USA; Duke Kunshan University, Kunshan City, Jiangsu Province, China.
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De Kesel PMM, Lambert WE, Stove CP. Alternative Sampling Strategies for Cytochrome P450 Phenotyping. Clin Pharmacokinet 2015; 55:169-84. [DOI: 10.1007/s40262-015-0306-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Oshikoya KA, Sammons H, Smith K, Choonara I. Lack of a significant change in caffeine metabolism in underweight children as determined by the caffeine breath test. Arch Dis Child 2015; 100:689-93. [PMID: 25897037 PMCID: PMC4483790 DOI: 10.1136/archdischild-2014-308017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 03/11/2015] [Accepted: 03/12/2015] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Limited data from pharmacokinetic studies in underweight and severely malnourished children have indicated an impaired activity of their hepatic enzymes. We used the caffeine breath test to assess the metabolising activity of cytochrome P450 1A2 (CYP1A2) enzyme in underweight children. METHODS Underweight children from the paediatric outpatient clinic, Lagos State University Teaching Hospital, Ikeja in Nigeria, were studied. After an overnight fast, 15 underweight children took 3 mg/kg labelled caffeine orally. Breath samples were collected in duplicate at -20, -10 and -1 min and at 15 min intervals for 2 h. The mean cumulative per cent dose recovered (CPDR) of labelled caffeine in the expired carbon dioxide was determined over the study period. This was repeated after 2-6 weeks of nutritional rehabilitation. RESULTS The mean areas under the enrichment-time curve before and after nutritional rehabilitation were 0.539±0.320 and 0.620±0.322 atom per cent excess minute, respectively. The difference between the two values was not statistically significant (p=0.528). The mean CPDR in the exhaled carbon dioxide of the underweight children over a period of 2 h was 7.56±4.01% and 7.95±3.68% before and after nutritional rehabilitation, respectively, and there was no significant difference in the mean values (p=0.603). CONCLUSIONS The metabolism of caffeine was not significantly affected in underweight children compared with after 2-6 weeks of nutritional rehabilitation. This suggests that hepatic CYP1A2-metabolising activity was not significantly impaired in underweight children.
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Affiliation(s)
- K A Oshikoya
- Academic Division of Child Health, Graduate Entry Medical School in Derby, University of Nottingham, Derby, UK Department of Pharmacology, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria
| | - H Sammons
- Academic Division of Child Health, Graduate Entry Medical School in Derby, University of Nottingham, Derby, UK
| | - K Smith
- Clinical Physiology Department Graduate Entry Medical School in Derby, University of Nottingham, Derby, UK
| | - I Choonara
- Academic Division of Child Health, Graduate Entry Medical School in Derby, University of Nottingham, Derby, UK
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Malinowski M, Jara M, Lüttgert K, Orr J, Lock JF, Schott E, Stockmann M. Enzymatic liver function capacity correlates with disease severity of patients with liver cirrhosis: a study with the LiMAx test. Dig Dis Sci 2014; 59:2983-91. [PMID: 24993690 DOI: 10.1007/s10620-014-3250-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 06/06/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Assessment and quantification of actual liver function is crucial in patients with chronic liver disease to monitor disease progression and predict individual prognosis. Mathematical models, such as model for end-stage liver disease, are used for risk stratification of patients with chronic liver disease but do not include parameters that reflect the actual functional state of the liver. AIM We aimed to evaluate the potential of a (13)C-based liver function test as a stratification tool by comparison with other liver function tests and clinical parameters in a large sample of healthy controls and cirrhotic patients. METHODS We applied maximum liver function capacity (LiMAx) to evaluate actual liver function in 347 patients with cirrhosis and in 86 controls. RESULTS LiMAx showed strong negative correlation with Child-Pugh Score (r = -0.707; p < 0.001), MELD (r = -0.686; p < 0.001) and liver function tests. LiMAx was lower in patients with liver cirrhosis compared to healthy controls [99 (57-160) µg/kg/h vs. 412 (365-479) µg/kg/h, p < 0.001] and differed among Child-Pugh classes [a: 181 (144-227) µg/kg/h, b: 96 (62-132) µg/kg/h and c: 52 (37-81) µg/kg/h; p < 0.001]. When stratified patients according to disease severity, LiMAx results were not different between cirrhotic patients and cirrhotic patients with transjugular intrahepatic portosystemic shunt. CONCLUSIONS LiMAx appears to provide reliable information on remnant enzymatic liver function in chronic liver disease and allows graduation of disease severity.
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Affiliation(s)
- Maciej Malinowski
- Department of General, Visceral and Transplantation Surgery, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany,
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15
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Pijls KE, de Vries H, Nikkessen S, Bast A, Wodzig WKWH, Koek GH. Critical appraisal of 13C breath tests for microsomal liver function: aminopyrine revisited. Liver Int 2014; 34:487-94. [PMID: 24428683 DOI: 10.1111/liv.12451] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 12/15/2013] [Indexed: 12/17/2022]
Abstract
As liver diseases are a major health problem and especially the incidence of metabolic liver diseases like non-alcoholic fatty liver disease (NAFLD) is rising, the demand for non-invasive tests is growing to replace liver biopsy. Non-invasive tests such as carbon-labelled breath tests can provide a valuable contribution to the evaluation of metabolic liver function. This review aims to critically appraise the value of the (13) C-labelled microsomal breath tests for the evaluation of metabolic liver function, and to discuss the role of cytochrome P450 enzymes in the metabolism of the different probe drugs, especially of aminopyrine. Although a number of different probe drugs have been used in breath tests, the perfect drug to assess the functional metabolic capacity of the liver has not been found. Data suggest that both the (13) C(2) -aminopyrine and the (13) C-methacetin breath test can play a role in assessing the capacity of the microsomal liver function and may be useful in the follow-up of patients with chronic liver diseases. Furthermore, CYP2C19 seems to be an important enzyme in the N-demethylation of aminopyrine, and polymorphisms in this gene may influence breath test values, which should be kept in mind when performing the (13) C(2) -aminopyrine breath test in clinical practice.
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Affiliation(s)
- Kirsten E Pijls
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
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16
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Albarmawi A, Czock D, Gauss A, Ehehalt R, Lorenzo Bermejo J, Burhenne J, Ganten TM, Sauer P, Haefeli WE. CYP3A activity in severe liver cirrhosis correlates with Child-Pugh and model for end-stage liver disease (MELD) scores. Br J Clin Pharmacol 2014; 77:160-169. [PMID: 23772874 PMCID: PMC3895357 DOI: 10.1111/bcp.12182] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 06/01/2013] [Indexed: 12/18/2022] Open
Abstract
AIMS Impaired liver function often necessitates drug dose adjustment to avoid excessive drug accumulation and adverse events, but a marker for the extent of the required adjustment is lacking. The aim of this study was to investigate whether Child-Pugh (CP) and model for end-stage liver disease (MELD) scores correlate with drug clearance. METHODS Midazolam was used as a CYP3A probe and its pharmacokinetics were analyzed in 24 patients with mild to severe liver cirrhosis (n = 4, 10 and 10 with CP class A, B and C, respectively) and six patients without liver disease. RESULTS Both scores correlated well with unbound midazolam clearance (CLu ), unbound midazolam fraction and half-life (all P < 0.01), whereas the unbound steady-state volume of distribution was not significantly changed. In patients with severe liver cirrhosis unbound midazolam clearance was only 14% of controls (CP C: CLu = 843 ± 346 l h(-1), MELD ≥ 15: CLu = 805 ± 474 l h(-1), controls: CLu = 5815 ± 2649 l h(-1), P < 0.01). CONCLUSION The correlation with unbound midazolam clearance suggests that either score predicts the metabolic capacity of CYP3A, the most relevant drug metabolizing enzyme subfamily in humans.
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Affiliation(s)
- Albader Albarmawi
- Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
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17
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Oshikoya KA, Smith K. Effect of Casilan(®) on (13)C-caffeine metabolism in overnight-fasted healthy Nigerian children. J Pharmacol Pharmacother 2013; 4:19-26. [PMID: 23662020 PMCID: PMC3643338 DOI: 10.4103/0976-500x.107648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Objective: To determine the effect of Casilan® on 13C-caffeine metabolism in healthy Nigerian children. Materials and Methods: Twelve healthy Nigerian children (male: six, female: six) aged 3–8 years were studied on three occasions. After an overnight fast, the children were studied after ingesting Casilan® only (Week 1). They were restudied after ingesting 3 mg/kg of labeled caffeine only (Week 2), and further re-studied after ingesting both Casilan® and labeled caffeine (Week 3). Breath samples were collected by blowing via a straw into an exentainer bottle. The cumulative percentage of 13C-caffeine exhaled as 13CO2 was measured over 2 h. Results: The time courses of 13C-enrichments in exhaled CO2 for all the children, after they had ingested labeled caffeine only and after they had ingested both Casilan® and labeled caffeine, were identical. There was a gradual rise and peak of the enrichments at about 60–75 min, followed by a gradual fall (II) or a plateau (III). Contrarily, the time course of 13C-enrichments for all the children was consistently low and stable after they had ingested Casilan® only (I). The mean values of cumulative percent 13C-doses recovered in the CO2 exhaled over a 2-h period, after ingesting labeled caffeine only (8.59 ± 1.10 δ%/mg) and after ingesting both Casilan® and labeled caffeine (8.58 ± 1.33 δ%/mg), were identical, with no statistically significant difference (P = 0.972). This suggests that Casilan® did not affect the CYP1A2 metabolic pathway. Conclusions: Casilan® is a safe, reliable and quantitative food supplement for overnight-fasted children undergoing caffeine breath test.
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Affiliation(s)
- Kazeem A Oshikoya
- Department of Child Health, Medical School in Derby, University of Nottingham, UK
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18
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Ahmad W, Ijaz B, Gull S, Asad S, Khaliq S, Jahan S, Sarwar MT, Kausar H, Sumrin A, Shahid I, Hassan S. A brief review on molecular, genetic and imaging techniques for HCV fibrosis evaluation. Virol J 2011; 8:53. [PMID: 21299910 PMCID: PMC3041775 DOI: 10.1186/1743-422x-8-53] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 02/08/2011] [Indexed: 02/08/2023] Open
Abstract
Background Chronic HCV is one of the major causes of morbidity and mortality in the present day world. The assessment of disease progression not only provides useful information for diagnosis and therapeutic supervision judgment but also for monitoring disease. Different invasive and non invasive methods are applied to diagnose the disease from initial to end stage (mild fibrosis to cirrhosis). Although, liver biopsy is still considered as gold standard to identify liver histological stages, an assessment of the disease development based on non-invasive clinical findings is also emerging and this may replace the need of biopsy in near future. This review gives brief insight on non-invasive methods currently available for predicting liver fibrosis in HCV with their current pros and cons to make easier for a clinician to choose better marker to assess liver fibrosis in HCV infected patients. Methods More than 200 studies regarding invasive and noninvasive markers available for HCV liver disease diagnosis were thoroughly reviewed. We examined year wise results of these markers based on their sensitivity, specificity, PPV, NPV and AUROCs. Results We found that in all non-invasive serum markers for HCV, FibroTest, Forn's Index, Fibrometer and HepaScore have high five-year predictive value but with low AUROCs (0.60~0.85) and are not comparable to liver biopsy (AUROC = 0.97). Even though from its beginning, Fibroscan is proved to be best with high AUROCs (> 0.90) in all studies, no single noninvasive marker is able to differentiate all fibrosis stages from end stage cirrhosis. Meanwhile, specific genetic markers may not only discriminate fibrotic and cirrhotic liver but also differentiate individual fibrosis stages. Conclusions There is a need of marker which accurately determines the stage based on simplest routine laboratory test. Genetic marker in combination of imaging technique may be the better non invasive diagnostic method in future.
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Affiliation(s)
- Waqar Ahmad
- Applied and Functional Genomics Laboratory, Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
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Abstract
Caffeine, theophylline, theobromine, and paraxanthine administered to animals and humans distribute in all body fluids and cross all biological membranes. They do not accumulate in organs or tissues and are extensively metabolized by the liver, with less than 2% of caffeine administered excreted unchanged in human urine. Dose-independent and dose-dependent pharmacokinetics of caffeine and other dimethylxanthines may be observed and explained by saturation of metabolic pathways and impaired elimination due to the immaturity of hepatic enzyme and liver diseases. While gender and menstrual cycle have little effect on their elimination, decreased clearance is seen in women using oral contraceptives and during pregnancy. Obesity, physical exercise, diseases, and particularly smoking and the interactions of drugs affect their elimination owing to either stimulation or inhibition of CYP1A2. Their metabolic pathways exhibit important quantitative and qualitative differences in animal species and man. Chronic ingestion or restriction of caffeine intake in man has a small effect on their disposition, but dietary constituents, including broccoli and herbal tea, as well as alcohol were shown to modify their plasma pharmacokinetics. Using molar ratios of metabolites in plasma and/or urine, phenotyping of various enzyme activities, such as cytochrome monooxygenases, N-acetylation, 8-hydroxylation, and xanthine oxidase, has become a valuable tool to identify polymorphisms and to understand individual variations and potential associations with health risks in epidemiological surveys.
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Affiliation(s)
- Maurice J Arnaud
- Nutrition and Biochemistry, Bourg-Dessous 2A, La Tour-de-Peilz, Switzerland.
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20
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Johnson TN, Boussery K, Rowland-Yeo K, Tucker GT, Rostami-Hodjegan A. A semi-mechanistic model to predict the effects of liver cirrhosis on drug clearance. Clin Pharmacokinet 2010; 49:189-206. [PMID: 20170207 DOI: 10.2165/11318160-000000000-00000] [Citation(s) in RCA: 168] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND OBJECTIVE Liver cirrhosis is characterized by a decrease in functional hepatocytes, lowered circulating levels of plasma proteins and alterations in blood flow due to the development of portacaval shunts. Depending on the interplay between these parameters and the characteristics of an administered drug, varying degrees of impaired systemic clearance and first-pass metabolism are anticipated. The Simcyp Population-based ADME Simulator has already been used successfully to incorporate genetic, physiological and demographic attributes of certain subgroups within healthy populations into in vitro-in vivo extrapolation (IVIVE) of xenobiotic clearance. The objective of this study was to extend population models to predict systemic and oral drug clearance in relation to the severity of liver cirrhosis. METHODS Information on demographics, changes in hepatic blood flow, cytochrome P450 enzymes, liver size, plasma protein binding and renal function was incorporated into three separate population libraries. The latter corresponded to Child-Pugh scores A (mild), B (moderate) and C (severe) liver cirrhosis. These libraries, together with mechanistic IVIVE within the Simcyp Simulator, were used to predict the clearance of intravenous and oral midazolam, oral caffeine, intravenous and oral theophylline, intravenous and oral metoprolol, oral nifedipine, oral quinidine, oral diclofenac, oral sildenafil, and intravenous and oral omeprazole. The simulated patients matched the clinical studies as closely as possible with regard to demographics and Child-Pugh scores. Predicted clearance values in both healthy control and liver cirrhosis populations were compared with observed values, as were the fold increases in clearance values between these populations. RESULTS There was good agreement (lack of statistically significant difference, two-tailed paired t-test) between observed and predicted clearance ratios, with the exception of those for two studies of intravenous omeprazole. Predicted clearance ratios were within 0.8- to 1.25-fold of observed ratios in 65% of cases (range 0.34- to 2.5-fold). CONCLUSION The various drugs that were studied showed different changes in clearance in relation to disease severity, and a 'one size fits all' solution does not exist without considering the multiple sources of the changes. Predictions of the effects of liver cirrhosis on drug clearance are of potential value in the design of clinical studies during drug development and, clinically, in the assessment of likely dosage adjustment.
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21
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Farrell G, Fan J. Prevention of Hepatocellular Carcinoma. HEPATOCELLULAR CARCINOMA 2009:36-61. [DOI: 10.3109/9780203092880-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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22
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Abstract
Although chronic infection with hepatitis B virus and/or hepatitis C virus are the most important risk factors for hepatocellular carcinoma (HCC) worldwide, other causes of cirrhosis can also lead to HCC. Given the high prevalence of alcoholism and the worldwide obesity epidemic, the relevant importance of nonviral liver disease-related HCC is expected to increase in the future. Some evidence supports mechanistic interactions between host or environmental factors and chronic viral hepatitis in the development of HCC. For example, food- and water-borne carcinogens have contributed to unusually high rates of HCC in parts of China and sub-Saharan Africa. With some of these conditions, appropriate public health measures to reduce the population's exposure to known etiologic agents, or early therapeutic intervention for 'at-risk' individuals before development of cirrhosis (e.g. hereditary hemochromatosis) can prevent HCC. Community-based programs to discourage and deal with excessive alcohol intake, to promote tobacco smoking awareness, to avoid exposure to aflatoxin and other food toxins, and measures to reduce the pandemic of obesity and diabetes are vital for effective interruption of the rising tide of HCC from nonviral liver disease.
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Affiliation(s)
- Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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23
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The 13C-caffeine breath test detects significant fibrosis in patients with nonalcoholic steatohepatitis. J Clin Gastroenterol 2008; 42:408-12. [PMID: 18277896 DOI: 10.1097/mcg.0b013e318046ea65] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The C-caffeine breath test (CBT) is a noninvasive tool for the evaluation of the cytochrome P450 system, implicated in the development of nonalcoholic steatohepatitis. GOAL To apply the CBT to assess the extent of hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). METHODS Twenty-six consecutive patients (mean age 56.1+/-6.85 y, 69.2% women) with NAFLD underwent the CBT, in addition to the clinical and laboratory evaluations and liver biopsy. Ten healthy individuals matched for age served as controls. RESULTS Mean delta over baseline values differed significantly between patients and controls (1.51+/-0.9 vs. 2.37+/-0.8 Delta per thousand/mg, respectively) (P=0.01) and were significantly higher in patients with fibrosis stage <2 (Brunt's system) (2.0+/-0.77 vs. 1.3+/-0.9 for stage > or =2, P=0.05). Mean delta over baseline values correlated highly with fibrosis stage (P=0.01), albumin (P=0.007), international normalized ratio (P=0.04), bilirubin (P=0.0008), and platelet count (P=0.0001). On multivariate stepwise logistic regression analysis, CBT was the best predictor of severe fibrosis (stage > or =2) (odds ratio 0.274, 95% confidence interval 0.086-0.872, P=0.028), with an area under the curve of 0.788. CONCLUSIONS The CBT is safe and easy to perform. It can reliably predict severe hepatic fibrosis in patients with NAFLD. Further large-scale studies are still needed.
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Gallardo-Wong I, Morán S, Rodríguez-Leal G, Castañeda-Romero B, Mera R, Poo J, Uribe M, Dehesa M. Prognostic value of 13C-phenylalanine breath test on predicting survival in patients with chronic liver failure. World J Gastroenterol 2007; 13:4579-85. [PMID: 17729409 PMCID: PMC4611830 DOI: 10.3748/wjg.v13.i34.4579] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the prognostic value of percentage of 13C-phenylalanine oxidation (13C-PheOx) obtained by 13C-phenylalanine breath test (13C-PheBT) on the survival of patients with chronic liver failure.
METHODS: The hepatic function was determined by standard liver blood tests and the percentage of 13C-PheOx in 118 chronic liver failure patients. The follow-up period was of 64 mo. Survival analysis was performed by the Kaplan-Meier method and variables that were significant (P < 0.10) in univariate analysis and subsequently introduced in a multivariate analysis according to the hazard model proposed by Cox.
RESULTS: Forty-one patients died due to progressive liver failure during the follow-up period. The probability of survival at 12, 24, 36, 48 and 64 mo was 0.88, 0.78, 0.66, 0.57 and 0.19, respectively. Multivariate analysis demonstrated that Child-Pugh classes, age, creatinine and the percentage of 13C-PheOx (HR 0.338, 95% CI: 0.150-0.762, P = 0.009) were independent predictors of survival. When Child-Pugh classes were replaced by all the parameters of the score, only albumin, bilirubin, creatinine, age and the percentage of 13C-PheOx (HR 0.449, 95% CI: 0.206-0.979, P = 0.034) were found to be independent predictors of survival.
CONCLUSION: Percentage of 13C-PheOx obtained by 13C-PheBT is a strong predictor of survival in patients with chronic liver disease.
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Affiliation(s)
- I Gallardo-Wong
- Laboratory of Gastrohepatology Research, Hospital de Pediatria, CMN, Siglo XXI, IMSS. Av Cuauhtemoc 330, Colonia Doctores, Delegacion Cuauhtemoc, Mexico
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Braden B, Lembcke B, Kuker W, Caspary WF. 13C-breath tests: current state of the art and future directions. Dig Liver Dis 2007; 39:795-805. [PMID: 17652042 DOI: 10.1016/j.dld.2007.06.012] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2007] [Revised: 06/14/2007] [Accepted: 06/28/2007] [Indexed: 12/11/2022]
Abstract
13C-breath tests provide a non-invasive diagnostic method with high patient acceptance. In vivo, human and also bacterial enzyme activities, organ functions and transport processes can be assessed semiquantitatively using breath tests. As the samples can directly be analysed using non-dispersive isotope selective infrared spectrometers or sent to analytical centres by normal mail breath tests can be easily performed also in primary care settings. The 13C-urea breath test which detects a Helicobacter pylori infection of the stomach is the most prominent application of stable isotopes. Determination of gastric emptying using test meals labelled with 13C-octanoic or 13C-acetic acid provide reliable results compared to scintigraphy. The clinical use of 13C-breath tests for the diagnosis of exocrine pancreatic insufficiency is still limited due to expensive substrates and long test periods with many samples. However, the quantification of liver function using hepatically metabolised 13C-substrates is clinically helpful in special indications. The stable isotope technique presents an elegant, non-invasive diagnostic tool promising further options of clinical applications. This review is aimed at providing an overview on the relevant clinical applications of 13C-breath tests.
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Affiliation(s)
- B Braden
- John Radcliffe Hospital, Headley Way, OX3 9DU Oxford, UK.
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Schneider A, Caspary WF, Saich R, Dietrich CF, Sarrazin C, Kuker W, Braden B. 13C-methacetin breath test shortened: 2-point-measurements after 15 minutes reliably indicate the presence of liver cirrhosis. J Clin Gastroenterol 2007; 41:33-37. [PMID: 17198062 DOI: 10.1097/mcg.0b013e31802dd4b9] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND GOALS The 13C-methacetin breath test (MBT) measures the activity of the cytochrome P450 dependent enzyme system and has been developed to assess the functional hepatic mass. We evaluated simple modifications of the 13C-MBT to further increase its practicability and therefore clinical acceptance. STUDY One hundred and four patients with different chronic liver diseases (including 35 patients with histologically proven cirrhosis) and 65 healthy controls underwent the 13C-MBT. Breath test results of 2-point measurements were compared with conventional breath test results (cumulative recovery after 30 min) and liver histology. RESULTS The 2-point-measurement at 0 and 15 minutes (with a cut-off <14.6 per thousand delta over baseline) had 92.6% sensitivity and 94.1% specificity in identifying the presence of cirrhosis compared with liver histology. The 2-point-measurements at 5 and 10 minutes also provided good discrimination between cirrhotic and noncirrhotic patients. CONCLUSIONS The 13C-MBT using 2-point-measurement of breath samples at baseline and after 15 minutes reliably indicates decreased liver function in liver cirrhosis. This simplification of the 13C-MBT will increase practicability and cost efficiency, thus facilitating its clinical acceptability.
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Affiliation(s)
- Arne Schneider
- Medical Department I, Johann Wolfgang Goethe University of Frankfurt/Main, Germany
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van der Poorten D, Kwok A, Lam T, Ridley L, Jones DB, Ngu MC, Lee AU. Twenty-year audit of percutaneous liver biopsy in a major Australian teaching hospital. Intern Med J 2006; 36:692-9. [PMID: 17040353 DOI: 10.1111/j.1445-5994.2006.01216.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND To examine the changes in indications, patient characteristics, safety and outcomes in consecutive patients undergoing percutaneous core liver biopsies in a major Australian teaching hospital over a period of two decades. METHODS A retrospective audit was carried out on all percutaneous core liver biopsies from a single institution between 1996 and 2005. This was combined with 10 years of data already reported on for the years 1986-1995 to detect trends in indications and outcomes. RESULTS Medical records from 1398 patients were included for analysis. Over a 20-year period, the most common indications for liver biopsy were hepatitis C (37.8%), hepatitis B (26.4%) and abnormal liver function tests (22.2%). Twelve major complications (1.0%) were seen; 10 episodes of haemorrhage, 1 bile leak and 1 visceral perforation. Seven of these patients had an abnormal baseline coagulation profile; a significant risk for major haemorrhage (P < 0.001), resulting in three deaths. All deaths occurred in inpatients with major comorbidities. Minor complications occurred in 13.6% of patients, with multiple passes a significant risk factor. Whereas the overall major and minor complication rates were independent of operator experience inadequate specimens were more frequently obtained by the registrar. CONCLUSION This large series extending over two decades shows that despite advances in biopsy techniques, the rates of both minor and major complications remain significant. Of particular concern are the procedure-related deaths. Identifying factors that may increase risk requires further scrutiny and careful patient selection needs to be undertaken.
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Affiliation(s)
- D van der Poorten
- Department of Gastroenterology and Hepatology, Concord Repatriation General Hospital, Sydney, Australia.
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Tarantino G, Conca P, Capone D, Gentile A, Polichetti G, Basile V. Reliability of total overnight salivary caffeine assessment (TOSCA) for liver function evaluation in compensated cirrhotic patients. Eur J Clin Pharmacol 2006; 62:605-612. [PMID: 16841221 DOI: 10.1007/s00228-006-0146-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2005] [Accepted: 04/07/2006] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Systemic caffeine clearance is considered the gold standard for phenotyping cytochrome P450 1A2 in epidemiological studies, and has been recommended for the non-invasive assessment of liver function in chronic liver disease. Our aim was to find a valid, simple and reliable alternative to this method, and therefore focused our attention on the measurement of an unique salivary caffeine concentration, without drug exposure. METHODS Our evaluation included 36 healthy controls, 47 patients with compensated liver cirrhosis of viral origin, and 48 obese and diabetic patients with cryptogenetic (likely metabolic) cirrhosis. All shared the same caffeine consumption habits (regular daily use of caffeinated beverages, mainly coffee). The total overnight salivary caffeine assessment (TOSCA) was determined by using a single-point concentration of salivary caffeine, after an overnight period of abstinence. RESULTS Daily routine caffeine intake of our population was adequate for studying the TOSCA. This single-point concentration correlated well with caffeine clearance, measured by salivary concentrations of caffeine. Mean TOSCA in cirrhotic patients was significantly higher than in controls (p<0.001; sensitivity (%) 84.2 and specificity (%) 97.2; negative likelihood ratio=0.16 and positive likelihood ratio=30.32). A cut-off set at 4.2 microg/ml (sensitivity (%) 95.8 and specificity (%) 68.1; negative likelihood ratio=0.06 and positive likelihood ratio=3.0) successfully differentiated the type of cirrhosis. Rapid (with higher metabolism of caffeine) metabolizers were more frequent in the group of patients with cirrhosis of metabolic origin (70.8%; p<0.0001), and the opposite was true for the group of patients with cirrhosis of viral origin, which comprised many poor metabolizers (85.1%; p<0.001). Serum transforming growth factor-beta 1 concentration, mirroring ongoing fibrosis, ranked high in poor metabolizers. The association between overnight assessment and homeostasis model assessment in rapid metabolizers could result from similar roles for cytochrome P450 1A2 and insulin resistance in determining metabolic liver cirrhosis. CONCLUSION The TOSCA, although differential between the viral and metabolic etiologies, could be considered a good diagnostic use to verify the presence and eventually the type of compensated liver cirrhosis.
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Affiliation(s)
- Giovanni Tarantino
- Department of Clinical and Experimental Medicine, Section of Hepatology in Internal Medicine, Federico II University Medical School, Naples, Italy.
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Thuluvath PJ, Krok KL. Noninvasive markers of fibrosis for longitudinal assessment of fibrosis in chronic liver disease: are they ready for prime time? Am J Gastroenterol 2006; 101:1497-9. [PMID: 16863552 DOI: 10.1111/j.1572-0241.2005.00304.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Over the past decade, there has been a renewed enthusiasm to develop noninvasive serum markers or tests to assess the presence and severity of fibrosis in chronic liver disease. Although a single marker or test has lacked the necessary accuracy to predict fibrosis, different combinations of these markers or tests have shown encouraging results. However, inter-laboratory variability and inconsistent results with liver diseases of varying etiologies have made it difficult to assess the reliability of these markers in clinical practice. In this issue of the journal, Poynard et al. describe the "histological" response to lamivudine in patients with chronic Hepatitis B Virus (HBV) over a 24-month period using surrogate serum biomarkers (Fibrotest-Actitest, FT-AT) without corroborating histological data. Investigators found improvement in fibrosis and inflammation in 85% and 91%, respectively, despite the emergence of YMDD mutation in 41.5% of patients. The higher improvement rates reported in this study should be interpreted with caution for a number of reasons including the absence of data on virological response rates, corroboratory histological data, and data on the validity of FT to evaluate fibrosis in a longitudinal manner. Although FT has been studied extensively by the authors of the current study, to date there are only few independent studies. In addition to significant inter-laboratory variations, these studies have shown that significant fibrosis could be missed, or conversely significant fibrosis diagnosed in the absence of minimal or no fibrosis in about 15% to 20% of patients. We may be approaching a time when serum biomarkers may become an integral part of the assessment of patients with chronic liver disease, but published evidence suggests that these markers are not yet ready for prime time.
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Gisbert JP, González-Lama Y. [Breath tests in the diagnosis of gastrointestinal diseases]. GASTROENTEROLOGIA Y HEPATOLOGIA 2005; 28:407-16. [PMID: 16137476 DOI: 10.1157/13077762] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Determination of carbon or hydrogen markers in breath has allowed closer investigation of the pathogenic mechanisms of several gastrointestinal diseases. Thus, the 13C-urea breath test is a nonaggressive, simple and safe test with excellent accuracy both in the initial diagnosis of Helicobacter pylori infection and in confirmation of its eradication following treatment. Moreover, because of the simplicity, reproducibility and safety of these types of procedure, they have tended to substitute more uncomfortable and expensive techniques that were traditionally used in gastroenterology. Several breath tests have been developed that allow reliable evaluation of liver or exocrine pancreatic function, gastrointestinal motility, as related to gastric emptying or orocecal transit time, and a diagnostic approach to clinical problems that could be due to bacterial overgrowth or malabsorption of various sugars.
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Affiliation(s)
- J P Gisbert
- Servicio de Aparato Digestivo, Hospital Universitario de la Princesa, Madrid, España.
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Park GJH, Katelaris PH, Jones DB, Seow F, Lin BPC, Le Couteur DG, Ngu MC. The C-caffeine breath test distinguishes significant fibrosis in chronic hepatitis B and reflects response to lamivudine therapy. Aliment Pharmacol Ther 2005; 22:395-403. [PMID: 16128677 DOI: 10.1111/j.1365-2036.2005.02623.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND The 13C-caffeine breath test is a non-invasive, quantitative test of liver function. AIM To determine the utility of the 13C-caffeine breath test in chronic hepatitis B virus and its ability to monitor response to lamivudine. METHODS Forty-eight chronic hepatitis B virus patients and 24 controls underwent the 13C-caffeine breath test. In 28 patients commenced on lamivudine, 13C-caffeine breath tests were performed at 1 week (n = 12) and after 1 year of therapy. RESULTS Patients with Metavir F0-1 fibrosis (2.30 +/- 1.02 Delta per thousand per 100 mg caffeine) had a 13C-caffeine breath test similar to controls (2.31 +/- 0.85, P = 0.96). However, patients with F2-3 fibrosis (1.59 +/- 0.78, P = 0.047) and cirrhotic patients (0.99 +/- 0.33, P = 0.001) had a decreased 13C-caffeine breath test. Fibrosis correlated best with the 13C-caffeine breath test (r(s) = -0.62, P < 0.001). The 13C-caffeine breath test independently predicted significant (F > or = 2) and advanced (F > or = 3) fibrosis and yielded the greatest area under the receiver operating characteristic curve (0.91 +/- 0.04) for predicting advanced fibrosis. The 13C-caffeine breath test was unaltered by 1 week of lamivudine but improved by 61% (P < 0.001) in responders to long-term lamivudine, whereas in those with viraemia and elevated alanine aminotransferase, values remained stable or deteriorated. CONCLUSION The 13C-caffeine breath test distinguishes chronic hepatitis B virus-related fibrosis and detects improvement in liver function in response to long-term lamivudine.
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Affiliation(s)
- G J-H Park
- Department of Gastroenterology and Hepatology, The University of Sydney, Concord Hospital, Concord, NSW, Australia.
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Thuluvath PJ, Krok KL. Noninvasive markers of fibrosis for longitudinal assessment of fibrosis in chronic liver disease: are they ready for prime time? Am J Gastroenterol 2005; 100:1981-3. [PMID: 16128942 DOI: 10.1111/j.1572-0241.2005.00284.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Over the past decade, there has been a renewed enthusiasm to develop noninvasive serum markers or tests to assess the presence and severity of fibrosis in chronic liver disease. Although a single marker or test has lacked the necessary accuracy to predict fibrosis, different combinations of these markers or tests have shown encouraging results. However, interlaboratory variability and inconsistent results with liver diseases of varying etiologies have made it difficult to assess the reliability of these markers in clinical practice. In this issue of the Journal, Poynard and colleagues describe the "histological" response to lamivudine in patients with chronic HBV over a 24-month period using surrogate serum biomarkers (FibroTest-ActiTest) without corroborating histological data. Investigators found improvement in fibrosis and inflammation in 85% and 91%, respectively, despite the emergence of YMDD mutation in 41.5% of patients. The higher improvement rates reported in this study should be interpreted with caution for a number of reasons including the absence of data on virological response rates, corroboratory histological data, and data on the validity of FibroTest to evaluate fibrosis in a longitudinal manner. Although FibroTest has been studied extensively by the authors of the current study, to date there are only few independent studies. In addition to significant interlaboratory variations, these studies have shown that significant fibrosis could be missed, or conversely significant fibrosis diagnosed in the absence of minimal or no fibrosis in about 15-20% of patients. We may be approaching a time when serum biomarkers may become an integral part of the assessment of patients with chronic liver disease, but published evidence suggests that these markers are not yet ready for prime time.
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Mullin EJ, Metcalfe MS, Maddern GJ. How much liver resection is too much? Am J Surg 2005; 190:87-97. [PMID: 15972178 DOI: 10.1016/j.amjsurg.2005.01.043] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2004] [Revised: 12/07/2004] [Accepted: 01/11/2005] [Indexed: 12/17/2022]
Abstract
BACKGROUND Hepatic failure occurring after liver resection carries a poor prognosis and is a complication dreaded by surgeons. Inadequate reserve in the remaining parenchyma leads to a steady decrease in liver function, inability to regenerate, and progression to liver failure. For this reason, many methods to quantify functional hepatic reserve have been developed. METHODS This article reviews the main methods used in the assessment of hepatic reserve in patients undergoing hepatectomy and their use in operative decision making. RESULTS A range of methods to categorically quantify the functional reserve of the liver have been developed, ranging from scoring systems (such as the Child-Pugh classification) to tests assessing complex hepatic metabolic pathways to radiological methods to assess functional reserve. However, no one method has or is ever likely to emerge as a single measure with which to dictate safe limits of resectability. CONCLUSIONS In the future, the role of residual liver function assessment may be of most benefit in the routine stratification of risk, thus enabling both patient consent to be obtained and surgical procedure to be performed, with full information and facts regarding operative risks. However, there is no one single test that remains conclusively superior.
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Affiliation(s)
- Emma J Mullin
- University of Adelaide, Department of Surgery, The Queen Elizabeth Hospital, Woodville, South Australia 5011, Australia
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Park G, Katelaris P, Jones DB, Ngu M, Le Couteur D. Caution before embracing serum markers of liver fibrosis in clinical practice. Gastroenterology 2005; 128:1145-6; author reply 1146. [PMID: 15825107 DOI: 10.1053/j.gastro.2005.02.044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Wan R, Wu YL, Wang H, Qu Q, Zhang S. Evaluation of hepatic function with 13C-methacetin breath test in patients with liver cirrhosis. Shijie Huaren Xiaohua Zazhi 2004; 12:2147-2149. [DOI: 10.11569/wcjd.v12.i9.2147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the characteristics of the 13C-methacetin breath test (13C-MBT) as a tool to monitor hepatic function of patients with liver cirrhosis.
METHODS: Forty-two patients with liver cirrhosis and thirty-one age- and sex-matched healthy controls underwent 13C-MBT.13C-methacetin (75 mg) was given orally, and the levels of 13CO2 delta over baseline (DOB), metabolisation velocity (MV) and cumulative percentage doses (CD) before and 10, 20, 30, 40, 50, 60, 80, 100 and 120 min after substrate administration breath samples was determined and compared, by non-dispersive infrared spectrometry.
RESULTS: The 13CO2 peak percent doses of healthy controls, Child class A and Child class B patients were 20.3 ±3.5%, 7.5±1.8% or 6.5±3.3% and 4.5±1.3%, and occurred at 20 min, 20 or 80 min and 40 min, respectively. The differences of13CO2 peak percent doses among healthy controls, Child class A and Child class B patients were obvious (P <0.05). No 13CO2peak percent doses occurred in Child class C patients. The differences of 13CO2 peak metabolic velocity were obvious (P <0.05) between healthy controls (28.8±5.3%) and Child class A patients (9.4±2.4%). No 13CO2 peak metabolic velocity occurred in Child class B and Child class C patients. The 13CO2 cumulative percentage doses of healthy controls, Child class A , Child class B and Child class C patients at 120 min after substrate administration were 31.2±4.5%, 13.8±3.7%, 8.2±2.2% and 2.4±0.8% (P <0.05), respectively.
CONCLUSION: The severity of liver damage can be directly and effectively evaluated by 13C-MBT in patients with cirrhosis.
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